The present invention relates to pyrrole derivatives exhibiting TGF-xcex2 inhibitory activity and being useful as fibrosis inhibitors for organs or tissues, a prodrug thereof, and pharmaceutically acceptable salts thereof.
Fibrosis of organs or tissues is induced by excessive accumulation of extracellular matrix within the organ, as repair or defenses, when said organ is invaded or damaged by some causes. The extracellular matrix is a substance surrounding the cells of tissues, and representative ones thereof are, for example, fibrinoproteins such as collagen, elastin, etc., complex carbohydrates such as proteoglycan, etc., glycoproteins such as fibronectin, laminin, etc. When the degree of the degeneration of organs, etc. by invasion or injury is not serious, then the organs, etc. can return to normality without any scarring of repair. However, when the degree of the degeneration of organs, etc. by invasion or injury is serious or the degeneration of organs persists, then the fibrosis of scarring of repair will further damage the original function of said organ, etc. And, further fibrosis is induced by said damage. Then, it falls into a vicious cycle thereof. Eventually, there will be caused a deficiency of organs, and at worst, the patient will die.
TGF-xcex2 (Transforming Growth Factor-xcex2) plays an important role in the accumulation of extracellular matrix. When TGF-xcex2 is administered to normal animals, there occurred many fibrotic events at various organs of said animals (International Review of Experimental Pathology, 34B: 43-67, 1993). In addition, it was reported that the fibrosis of tissues was observed in transgenic mice which highly express TGF-xcex2 (Proc. Natl. Acad. Sci. USA, 92:2572-2576, 1995; Laboratory Investigation, 74:991-1003, 1995).
TGF-xcex2 participates in the fibrosis of tissues in the following manner:
(1) Acting on cells, the extracellular matrix such as fibronectin (Journal of Biological Chemistry, 262:6443-6446, 1987), collagen (Proc. Natl. Acad. Sci. USA, 85:1105-1108, 1988), proteoglycan (Journal of Biological Chemistry, 263:3039-3045, 1988), etc. is potently produced:
(2) Decreasing the expression of an enzyme for degrading extracellular matrix (Journal of Biological Chemistry, 263:16999-17005, 1988) and potently promoting the expression of inhibitors of the extracelluar matrix degrading enzyme (Cancer Research, 49:2533-2553, 1989), by which the degradation of extracellular matrix is inhibited:
(3) Proliferating cells producing extracellular matrix (American Journal of Physiology, 264:F199-F205, 1993).
Thus, the inhibition of TGF-xcex2 is a useful means for inhibiting the accumulation of extracellular matrix. In fact, it is reported that the fibrosis is alleviated by administering antiserum of TGF-xcex2 to animal models for fibrosis (Nature, 346:371-374, 1990).
An object of the present invention is to provide a compound being useful as fibrosis inhibitors for organs or tissues. In order to solve the above problems, the present inventors have intensively studied, and found that pyrrole derivatives inhibit the fibrosis of organs or tissues, and have accomplished the present invention.
The present invention is as follows:
[1] A pyrrole derivative of the formula: 
xe2x80x83wherein Ring Z is an optionally substituted pyrrole ring, an optionally substituted indole ring, an optionally substituted thiophene ring, an optionally substituted pyrazole ring, an optionally substituted benzene ring, an optionally substituted imidazole ring, or an optionally substituted isothiazole ring;
W2 is xe2x80x94COxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94CONRxe2x80x94, an optionally substituted C1-C4 alkylene or an optionally substituted C2-C4 alkenylene, and R is hydrogen or an alkyl;
Ar2 is an optionally substituted aryl or an optionally substituted heteroaryl;
W1 and Ar1 mean the following (1) or (2):
(1) W1 is an optionally substituted C1-C4 alkylene or an optionally substituted C2-C4 alkenylene; Ar1 is an optionally substituted bicyclic heteroaryl having 1 to 4 nitrogen atoms as ring-forming atoms:
(2) W1 is an optionally substituted C2-C5 alkylene, an optionally substituted C2-C5 alkenylene, an optionally substituted C2-C5 alkynylene, or xe2x80x94Yxe2x80x94W3xe2x80x94, Y is an oxygen atom or a cycloalkanediyl, and W3 is an optionally substituted C1-C5 alkylene, an optionally substituted C2-C5 alkenylene, or an optionally substituted C2-C5 alkynylene; and Ar1 is an aryl or monocyclic heteroaryl, which is substituted at the ortho- or meta-position thereof with respect to the binding position of W1 by a group selected from carboxyl, an alkoxycarbonyl, a carbamoyl having optionally alkyl-substituent(s), a cyclic aminocarbonyl, an alkyl-sulfonylcarbamoyl, an arylsulfonylcarbamoyl, an alkylsulfonyl, a sulfamoyl having optionally alkyl-substituent(s), a cyclic aminosulfonyl, tetrazolyl, cyano, an alkoxy and an alkylsulfonylamino, and said aryl or monocyclic heteroaryl being optionally further substituted, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
[2] The pyrrole derivative according to the above [1], wherein the divalent group including Ring Z may be any one of the following divalent groups (any direction of bonds is included), or a prodrug thereof, or a pharmaceutically acceptable salt thereof. 
wherein the number of R1 is one or more, and each is independently hydrogen, a halogen or an optionally substituted alkyl.
[3] The pyrrole derivative according to the above [1] or [2], wherein Ring Z is an optionally substituted pyrrole ring, an optionally substituted indole ring or an optionally substituted thiophene ring, or a prodrug, or a pharmaceutically acceptable salt thereof.
[4] The pyrrole derivative according to the above [1], which is a compound of the formula: 
wherein W1, W2, Ar1, Ar2 and R1 are as defined above, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
[5] The pyrrole derivative according to any one of the above [1] to [4], wherein W2 is xe2x80x94COxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94CONRxe2x80x94, methylene, or hydroxymethylene, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
[6] The pyrrole derivative according to any one of the above [1] to [5], wherein Ar2 is a substituted phenyl, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
[7] The pyrrole derivative according to any one of the above [1] to [6], wherein W1 is an optionally substituted C2-C5 alkylene, an optionally substituted C2-C5 alkenylene, or an optionally substituted C2-C5 alkynylene; and Ar1 is an aryl, which is substituted at the ortho-position thereof with respect to the binding position of W1 by a group selected from carboxyl, an alkoxycarbonyl, a carbamoyl having optionally alkyl-substituent(s), a cyclic aminocarbonyl, an alkylsulfonylcarbamoyl, an arylsulfonylcarbamoyl, an alkylsulfonyl, a sulfamoyl having optionally alkyl-substituent(s), a cyclic aminosulfonyl, tetrazolyl, cyano, an alkoxy and an alkylsulfonylamino, and said aryl being optionally further substituted,
or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
[8] The pyrrole derivative according to any one of the above [1] to [6], wherein W1 is an optionally substituted trans-C3-C4 alkenylene; and Ar1 is an aryl, which is substituted at the ortho-position thereof with respect to the binding position of W1 by a group selected from carboxyl, an alkoxycarbonyl, a carbamoyl having optionally alkyl-substituent(s), a cyclic aminocarbonyl, an alkylsulfonylcarbamoyl, an arylsulfonylcarbamoyl, tetrazolyl, cyano, an alkoxy and an alkylsulfonylamino, and said aryl being optionally further substituted by a halogen, cyano, an optionally substituted alkoxy or an optionally substituted alkyl,
or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
[9] The compound according to the above [1], which is a compound of the formula: 
xe2x80x83wherein W4 is xe2x80x94COxe2x80x94, xe2x80x94CONRxe2x80x94 or methylene, R is as defined above;
R2 is a halogen, cyano, an optionally substituted alkoxy or an optionally substituted alkyl;
R3 is hydroxyl, an alkoxy, an amino having optionally alkyl-substituent(s), a cyclic amino or an alkylsulfonylamino;
R4 is hydrogen, a halogen or an alkyl;
R5 is an optionally substituted alkoxy or an optionally substituted alkyl,
or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
[10] The compound according to the above [9], wherein W4 is xe2x80x94COxe2x80x94; R2 is a halogen, cyano, an alkoxy being optionally substituted by a halogen or an alkoxy, or an alkyl being optionally substituted by a halogen or an alkoxy; R4 is hydrogen or an alkyl; R5 is an alkoxy being optionally substituted by a halogen, an alkoxy or morpholino, or an alkyl being optionally substituted by a halogen, an alkoxy or morpholino, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
[11] The compound according to the above [9] or [10], which is a compound of the formula: 
xe2x80x83wherein R3 and R5 are as defined above,
or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
[12] A pyrrole derivative of the formula: 
xe2x80x83wherein R14 and R15 are independently hydrogen or an optionally substituted alkyl;
R11, R12 and R13 are as follows:
(1) R11 is xe2x80x94W11xe2x80x94Ar3 or xe2x80x94W12xe2x80x94Het, one of R12 and R13 is xe2x80x94W13xe2x80x94A, and the other is hydrogen or an optionally substituted alkyl, W11 is an optionally substituted C2-C5 alkylene or an optionally substituted C2-C5 alkenylene, W12 is an optionally substituted C1-C4 alkylene, W13 is xe2x80x94COxe2x80x94, an optionally substituted C1-C6 alkylene, or an optionally substituted C2-C5 alkenylene; or
(2) R11 is xe2x80x94W21xe2x80x94A, one of R12 and R13 is xe2x80x94W22xe2x80x94Ar3 or xe2x80x94W23xe2x80x94Het, and the other is hydrogen or an optionally substituted alkyl, W21 is an optionally substituted C1-C6 alkylene, an optionally substituted C2-C5 alkenylene, or xe2x80x94SO2xe2x80x94, W22 is an optionally substituted C2-C5 alkylene, or an optionally substituted C2-C5 alkenylene, W23 is xe2x80x94COxe2x80x94 or an optionally substituted C1-C4 alkylene, Ar3 is an aryl being substituted by xe2x80x94COR16, xe2x80x94SO2R17 or tetrazolyl, and said aryl being optionally further substituted by hydroxy, an optionally substituted C1-C4 alkyl, an optionally substituted C2-C4 alkenyl, an optionally substituted C2-C4 alkynyl, an optionally substituted C1-C4 alkoxy, a halogen, cyano, a carbamoyl having optionally alkyl-substituent(s), or a cyclic aminocarbonyl;
Het is an optionally substituted monocyclic or bicyclic heteroaryl having 1 to 4 nitrogen atoms as ring-forming atoms;
A is an optionally substituted aryl, or an optionally substituted monocyclic or bicyclic heteroaryl;
R16 is hydroxyl, an alkoxy, an amino having optionally alkyl-substituent(s), a cyclic amino, or an alkylsulfonylamino;
R17 is an alkyl, an amino having optionally alkyl-substituent(s), or a cyclic amino;
or a pharmaceutically acceptable salt thereof.
[13] The pyrrole derivative according to the above [12], wherein R11, R12 and R13 mean as follows:
R11 is xe2x80x94W11xe2x80x94Ar3 or xe2x80x94W12xe2x80x94Het;
one of R12 and R13 is xe2x80x94W13xe2x80x94A, and the other is hydrogen or an optionally substituted C1-C4 alkyl;
W11 is an optionally substituted C2-C5 alkenylene;
W12 is an optionally substituted C1-C4 alkylene;
W13 is xe2x80x94COxe2x80x94, an optionally substituted C1-C6 alkylene, or an optionally substituted C2-C5 alkenylene;
Ar3 is an aryl being substituted at the ortho-position thereof with respect to the binding position of W11 by a group selected from xe2x80x94COR16, xe2x80x94SO2R17 and tetrazolyl, and said aryl being optionally further substituted by a group selected from hydroxy, an optionally substituted C1-C4 alkyl, an optionally substituted C2-C4 alkenyl, an optionally substituted C2-C4 alkynyl, an optionally substituted C1-C4 alkoxy, a halogen, cyano, a carbamoyl having optionally C1-C4 alkyl-substituent(s), and a cyclic aminocarbonyl;
Het is an optionally substituted 3-quinolyl, an optionally substituted 3-naphthyridinyl or an optionally substituted 2-quinoxalyl;
A is an optionally substituted aryl, or an optionally substituted monocyclic or bicyclic heteroaryl;
R16 is hydroxy, a C1-C4 alkoxy, an amino having optionally C1-C4 alkyl-substituent(s), a cyclic amino, or a C1-C4 alkylsulfonylamino;
R17 is a C1-C4 alkyl, an amino having optionally C1-C4 alkyl-substituent(s), or a cyclic amino.
[14] A medicament containing the pyrrole derivative according to any one of the above [1] to [13], or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
[15] The medicament according to the above [14], which is a TGF-xcex2 inhibitor.
[16] The medicament according to the above [14], which is a fibrosis inhibitor.
The number of the substituents on the xe2x80x9csubstituted pyrrole ringxe2x80x9d, xe2x80x9csubstituted indole ringxe2x80x9d, xe2x80x9csubstituted thiophene ringxe2x80x9d, xe2x80x9csubstituted pyrazole ringxe2x80x9d, xe2x80x9csubstituted benzene ringxe2x80x9d, xe2x80x9csubstituted imidazole ringxe2x80x9d and xe2x80x9csubstituted isothiazole ringxe2x80x9d is 1 or more, for example, 2 or 3, and the substituents include the same groups for R1 except for hydrogen, i.e., a halogen or an optionally substituted alkyl.
The xe2x80x9calkylxe2x80x9d includes, for example, a straight chain or branched chain C1-C6 alkyl group, such as methyl, ethyl, 2-propyl, 2-methyl-1-propyl, butyl, 2-butyl, t-butyl, pentyl, 3-methyl-2-butyl, 2-methyl-2-butyl, hexyl, etc., and preferably a straight chain or branched chain C1-C4 alkyl.
The substituent of the xe2x80x9csubstituted alkyl for R2 and R5xe2x80x9d includes, for example, hydroxy, an alkanoyloxy, a halogen, cyano, an alkanoyl, an alkoxy, an alkoxycarbonyl, carboxy, an amino having optionally alkyl-substituent(s), an amino having optionally alkoxyalkyl-substituent(s), a cyclic amino, a monocyclic heteroaryl, a carbamoyl having optionally alkyl-substituent(s), a cyclic aminocarbonyl, a sulfamoyl having optionally alkyl-substituent(s), a cyclic aminosulfonyl, azide, etc. The number of the substituents may be one or more, for example, 2 or 3, and the substituents are the same or different. The preferable substituents of the substituted alkyl for R2 are a halogen, an alkoxy, etc. The preferable substituents of the substituted alkyl for R5 are a halogen, an alkoxy, morpholino, hydroxy, etc.
The substituent of the xe2x80x9csubstituted alkyl for R1, R12, R13, R14 and R15xe2x80x9d includes, for example, a halogen, an alkoxy, hydroxy, oxo, etc., and the number of the substituents are one or more, for example, 2 or 3, and the substituents may be the same or different.
The xe2x80x9calkoxyxe2x80x9d includes, for example, a straight chain or branched chain C1-C6 alkoxy, such as methoxy, ethoxy, propyloxy, 2-propyloxy, 2-methyl-2-propyloxy, butoxy, pentyloxy, hexyloxy, etc. and preferably a straight chain or branched chain C1-C4 alkoxy.
The substituent of the xe2x80x9csubstituted alkoxy for R2 and R5xe2x80x9d is, for example, hydroxy, an alkanoyloxy, a halogen, cyano, an alkanoyl, an alkoxy, an alkoxycarbonyl, carboxy, an amino having optionally alkyl-substituent(s), an amino having optionally alkoxyalkyl-substituent(s), a cyclic amino, a monocyclic heteroaryl, a carbamoyl having optionally alkyl-substituent(s), a cyclic aminocarbonyl, a sulfamoyl having optionally alkyl-substituent(s), a cyclic aminosulfonyl, azide, etc. The number of the substituents may be one or more, for example, 2 or 3, and the substituents may be the same or different. The preferable substituents of the substituted alkoxy for R2 are a halogen, an alkoxy, etc. The preferable substituents of the substituted alkoxy for R5 are a halogen, an alkoxy, morpholino, hydroxy, etc., and especially preferable substituted alkoxy is 2-morpholinoethoxy, etc.
The xe2x80x9calkanoylxe2x80x9d includes, for example, a straight chain or branched chain C1-C6 alkanoyl, such as formyl, acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl, hexanoyl, etc., and preferably a straight chain or branched chain C2-C5 alkanoyl.
The xe2x80x9calkenylxe2x80x9d includes, for example, a straight chain or branched chain C2-C6 alkenyl, such as vinyl, allyl, isopropenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-hexenyl, etc., and preferably a straight chain or branched chain C2-C4 alkenyl.
The xe2x80x9calkenyloxyxe2x80x9d includes, for example, a straight chain or branched chain C3-C6 alkenyloxy, such as allyloxy, 3-butenyloxy, 2-butenyloxy, etc., and preferably a straight chain or branched chain C3-C4 alkenyloxy.
The xe2x80x9calkynylxe2x80x9d includes, for example, a straight chain or branched chain C2-C6 alkynyl, such as ethynyl, 2-propynyl, 1-propynyl, 3-butynyl, 2-butynyl, 2-pentynyl, 3-hexynyl, etc., and preferably a straight chain or branched chain C2-C4 alkynyl.
The xe2x80x9calkynyloxyxe2x80x9d includes, for example, a straight chain or branched chain C3-C6 alkynyloxy, such as allyloxy, 3-butynyloxy, 2-butynyloxy, 3-pentynyloxy, etc., and preferably a straight chain or branched chain C3-C4 alkynyloxy.
The xe2x80x9calkylenexe2x80x9d includes, for example, a straight chain alkylene having carbon atoms in a number, within the scope of each, alkylene, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, etc.
Preferable examples of the xe2x80x9cC1-C4 alkylene for W2xe2x80x9d are methylene and ethylene, and especially preferable one is methylene.
Preferable examples of the xe2x80x9cC1-C4 alkylene for W1 when Ar1 is an optionally substituted bicyclic heteroaryl having 1 to 4 nitrogen atoms as ring-forming atomsxe2x80x9d are methylene, etc.
Preferable examples of the xe2x80x9cC2-C5 alkylene for W1, when Ar1 is an aryl or monocyclic heteroaryl, which is substituted at the ortho- or meta-position thereof with respect to the binding position of W1 by a group selected from carboxyl, an alkoxycarbonyl, a carbamoyl having optionally alkyl-substituent(s), a cyclic aminocarbonyl, an alkyl-sulfonylcarbamoyl, an arylsulfonylcarbamoyl, an alkylsulfonyl, a sulfamoyl having optionally alkyl-substituent(s), a cyclic aminosulfonyl, tetrazolyl, cyano, an alkoxy and an alkylsulfonylamino, and said aryl or monocyclic heteroaryl being optionally further substitutedxe2x80x9d are trimethylene, tetramethylene, etc.
Preferable examples of xe2x80x9cC1-C5 alkylene for W3xe2x80x9d are methylene, ethylene, etc.
The substituents of the xe2x80x9csubstituted alkylenexe2x80x9d includes, for example, an alkyl, an alkoxy, hydoxy, an alkanoyloxy, a halogen, etc., and the substituted alkylene has 1 or 2 substituents, which are the same or different.
The xe2x80x9calkenylenexe2x80x9d includes, for example, a straight chain alkenylene having carbon atoms in a number within the scope of each alkenylene, such as vinylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 1-pentenylene, 2-pentenylene, 3-pentenylene, 4-pentenylene, 2,4-pentadienylene, etc. The configuration at the double bonds may be either cis-configuration or trans-configuration, and preferable configuration is trans-configuration.
Preferable examples of the xe2x80x9cC2-C5 alkenylene for W1, when Ar1 is an aryl or monocyclic heteroaryl, which is substituted at the ortho- or meta-position thereof with respect to the binding position of W1 by a group selected from carboxyl, an alkoxycarbonyl, a carbamoyl having optionally alkyl-substituent(s), a cyclic aminocarbonyl, an alkyl-sulfonylcarbamoyl, an arylsulfonylcarbamoyl, an alkylsulfonyl, a sulfamoyl having optionally alkyl-substituent(s), a cyclic aminosulfonyl, tetrazolyl, cyano, an alkoxy and an alkylsulfonylamino, and said aryl or monocyclic heteroaryl being optionally further substitutedxe2x80x9d are a straight chain trans-C3-C4 alkenylene, and especially preferable example is trans-2-propenylene.
The xe2x80x9cC2-C5 alkynylenexe2x80x9d includes, for example, a straight chain C2-C5 alkynylene, such as ethynylene, 2-propynylene, 2-butynylene, 3-butynylene, 2-pentynylene, 3-pentynylene, etc.
The substituents of the xe2x80x9csubstituted alkenylenexe2x80x9d and the xe2x80x9csubstituted alkynylenexe2x80x9d are, for example, an alkyl, etc., and these groups have independently 1 or 2 substituents.
The xe2x80x9carylxe2x80x9d includes, for example, a C6-C10 aryl, such as phenyl, 1-naphthyl, 2-naphthyl, etc., and preferably one is phenyl.
The xe2x80x9cheteroarylxe2x80x9d includes, for example, a monocyclic or bicyclic heteroaryl having 1 to 3 heteroatom selected from a nitrogen, an oxygen and a sulfur, and these heteroatoms are the same or different, such as a monocyclic 5-membered heteroaryl (e.g., thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, etc.), a monocyclic 6-membered heteroaryl (e.g., pyridine, pyrimidine, pyrazine, pyridazine, triazine, etc.), a bicyclic heteroaryl (e.g., indole, isoindole, indolidine, indazole, purine, 4-H-quinolidine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, benzothiazole, benzoxazole, benzisothiazole, benzisoxazole, benzofuran, benzothiophene, etc.), etc.
The xe2x80x9cmonocyclic heteroarylxe2x80x9d includes monocyclic heteroaryls among heteroaryls.
Preferable examples of the xe2x80x9cmonocyclic heteroaryl for Ar1xe2x80x9d are a monocyclic heteroaryl being weak basic (pKb less than 7), and more preferable ones are a monocyclic 5-membered heteroaryl containing a sulfur atom or an oxygen atom, and especially preferable ones are thiophene, furan, thiazole, oxazole, isothiazole, isoxazole, etc.
Preferable examples of the xe2x80x9cheteroaryl for Ar2xe2x80x9d are a heteroaryl being weak basic (pKb less than 7), and more preferable ones are a monocyclic 5-membered heteroaryl and bicyclic heteroaryl containing a sulfur atom or an oxygen atom, and especially preferable ones are thiophene, furan, thiazole, oxazole, isothiazole, isoxazole, indole, isoindole, benzothiazole, benzoxazole, benzisothiazole, benzisoxazole, benzofuran, benzothiophene, etc.
The xe2x80x9cmonocyclic or bicyclic heteroaryl having 1 to 4 nitrogen atoms as ring-forming atomsxe2x80x9d includes, for example, a monocyclic 5-membered heteroaryl (e.g., pyrrolyl, imidazolyl, 3H-pyrazolyl, tetrazolyl, etc.), a monocyclic 6-membered heteroaryl (e.g., pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, etc.), a bicyclic heteroaryl (e.g., indolyl, isoindolyl, indolidinyl, indazolyl, puryl, 4-H-quinolidinyl, quinolinyl, isoquinolinyl, phthalazinyl, naphthyridyl, quinoxalyl, quinazolyl, etc.), etc. Preferable examples are a bicyclic heteroaryl, and more preferable ones are quinolyl, quinoxalyl, naphthyridyl, etc., and especially preferable ones are 3-quinolyl, 2-quinoxalyl, 3-naphthyridyl, etc.
The substituents of the xe2x80x9csubstituted arylxe2x80x9d, xe2x80x9csubstituted phenylxe2x80x9d, xe2x80x9csubstituted heteroarylxe2x80x9d, xe2x80x9csubstituted monocyclic or bicyclic heteroarylxe2x80x9d, xe2x80x9cmonocyclic or bicyclic heteroaryl having substituted 1 to 4 nitrogen atomsxe2x80x9d, xe2x80x9csubstituted 3-quinolylxe2x80x9d, xe2x80x9csubstituted 3-naphthyridylxe2x80x9d and xe2x80x9csubstituted 2-quinoxalylxe2x80x9d, and the other substituents of the xe2x80x9csubstituted aryl and substituted monocyclic heteroaryl for Ar1xe2x80x9d are exemplified as follows. These groups may have one or more, for example, 2 or 3 substituents, which are the same or different.
Optionally substituted alkyl
(the substituents of this substituted alkyl include, for example, hydroxy, an alkanoyloxy, a halogen, cyano, an alkanoyl, an alkoxy, an alkoxycarbonyl, carboxy, an amino having optionally alkyl-substituent(s), an amino having optionally alkoxyalkyl-substituent(s), a cyclic amino, a monocyclic heteroaryl, a carbamoyl having optionally alkyl-substituent(s), a cyclic aminocarbonyl, a sulfamoyl having optionally alkyl-substituent(s), a cyclic aminosulfonyl, azide, etc. The number of the substituents is 1 or more, for example, 2 or 3, and the substituents are the same or different.)
Optionally substituted alkoxy:
(the substituents of this substituted alkoxy include, for example, hydroxy, an alkanoyloxy, a halogen, cyano, an alkanoyl, an alkoxy, an alkoxycarbonyl, carboxy, an amino having optionally alkyl-substituent(s), an amino having optionally alkoxyalkyl-substituent(s), a cyclic amino, a monocyclic heteroaryl, a carbamoyl having optionally alkyl-substituent(s), a cyclic aminocarbonyl, a sulfamoyl having optionally alkyl-substituent(s), a cyclic aminosulfonyl, azide, etc. The number of the substituents is 1 or more, for example, 2 or 3, and the substituents are the same or different.)
Optionally substituted alkenyl, optionally substituted alkynyl:
(the substituents of these substituted alkenyl and substituted alkynyl include, for example, an alkoxy, an alkoxycarbonyl, an alkanoyl, hydroxy, an alkanoyloxy, a halogen, cyano, a carbamoyl having optionally alkyl-substituent(s), a cyclic aminocarbonyl, carboxy, an amino having optionally alkyl-substituent(s), a cyclic amino, a sulfamoyl having optionally alkyl-substituent(s), a cyclic aminosulfonyl, etc. The number of the substituents is 1 or more, for example, 2 or 3, and the substituents are the same or different.)
An alkenyloxy, hydroxy, an alkanoyl, an alkanoyloxy, a halogen, an alkylsulfonyl, an amino having optionally alkyl-substituent(s), a cyclic amino, a carbamoyl having optionally alkyl-substituent(s), a cyclic aminocarbonyl, a sulfamoyl having optionally alkyl-substituent(s), a cyclic aminosulfone, cyano, methylenedioxy, a heteroaryl, 1,3-dioxan-2-yl, etc.
Preferable examples of the substituents of the xe2x80x9csubstituted aryl for Ar2 and Axe2x80x9d, xe2x80x9csubstituted phenyl for Ar2xe2x80x9d, xe2x80x9csubstituted heteroaryl for Ar2xe2x80x9d and xe2x80x9csubstituted monocyclic or bicyclic heteroaryl for Axe2x80x9d are an optionally substituted alkyl, an optionally substituted alkoxy, hydroxy, morpholino, etc. More preferable examples are an optionally substituted alkyl (the substituents of the substituted alkyl is a halogen, an alkoxy, morpholino, hydroxy, etc.), a substituted alkoxy (the substituents of the substituted alkoxy is a halogen, an alkoxy, morpholino, hydroxy, etc.), hydroxy, etc., and especially perferable ones are methyl, methoxy, 2-morpholinoethoxy, hydroxy, etc. When Ar2 and A are a substituted phenyl, then the substitution position of these substituents is preferably para-position with respect to the binding position of W13 or W21, respectively.
Preferable examples of the substituents of the xe2x80x9csubstituted monocyclic or bicyclic heteroaryl containing 1 to 4 nitrogen atoms as ring-forming atoms for Ar1 and Hetxe2x80x9d, xe2x80x9csubstituted 3-quinolyl for Hetxe2x80x9d, xe2x80x9csubstituted 3-naphthyridyl for Hetxe2x80x9d, and xe2x80x9csubstituted 2-quinoxalyl for Hetxe2x80x9d, and the other substituents of the xe2x80x9csubstituted aryl and substituted monocyclic heteroaryl for Ar1 xe2x80x9d are a halogen, cyano, an optionally substituted alkyl, an optionally substituted alkoxy, etc. More preferable examples are a halogen, an optionally substituted alkyl (the substituent of the substituted alkyl is a halogen, an alkoxy, etc.), a substituted alkoxy (the substituent of the substituted alkyl is a halogen, an alkoxy, etc.), cyano, etc., and especially preferable examples are a halogen, an alkyl, an alkoxy, cyano, etc., and further most preferable examples are chlorine, methyl, cyano, etc. When Ar1 is a substituted phenyl, the substitution position of these substituents is preferably para-position with respect to the binding position of W1.
The substituents of the xe2x80x9csubstituted C1-C4 alkyl, substituted C2-C4 alkenyl, substituted C2-C4 alkynyl, and substituted C1-C4 alkoxy, which are substituents for aryl for Ar3xe2x80x9d are, for example, an alkoxy, an alkoxycarbonyl, an alkanoyl, hydroxy, an alkanoyloxy, a halogen, cyano, a carbamoyl having optionally alkyl-substituent(s), a cyclic amino-carbonyl, carboxy, an amino having optionally alkyl-substituent(s), a cyclic amino, a sulfamoyl having optionally alkyl-substituent(s), a cyclic aminosulfonyl, etc. The number of the substituents of these groups is 1 or more, for example, 2 or 3, and the substituents are the same or different.
In the aryl or monocyclic heteroaryl for Ar1, the ortho- or meta-position with respect to the binding position of W1 means a position adjacent to the binding position of W1 and further a position adjacent thereto, respectively. For example, the ortho-, meta- and para-positions are indicated below in cases wherein Ar1 is phenyl: 
The xe2x80x9chalogenxe2x80x9d is fluorine, chlorine, bromine, etc.
The xe2x80x9ccycloalkanediylxe2x80x9d includes, for example, a C3-C6 cyclo-alkanediyl, such as 1,2-cyclopropanediyl, 1,2-cyclobutanediyl, 1,2-cyclopentanediyl, 1,2-cyclohexanediyl, 1,3-cyclohexanediyl, 1,4-cyclohexanediyl, etc.
In the xe2x80x9camino having optionally alkyl-substituent(s)xe2x80x9d, xe2x80x9camino being optionally substituted by an alkoxyalkylxe2x80x9d, xe2x80x9ccarbamoyl having optionally alkyl-substituent(s)xe2x80x9d, and xe2x80x9csulfamoyl having optionally alkyl-substituent(s)xe2x80x9d, when these groups are substituted by an alkyl or an alkoxyalkyl, then these groups can be substituted by 1 or 2 alkyls or alkoxyalkyls which are the same or different.
The xe2x80x9ccyclic aminoxe2x80x9d includes a 5- to 7-membered cyclic amino optionally containing an oxygen atom, a sulfur atom or a nitrogen atom as ring-forming atoms, and this cyclic amino may be further substituted by an alkyl, hydroxy, etc., for example, pyrrolidino, piperidino, piperazinyl, 4-methylpiperazinyl, morpholino, thiomorpholino, 4-hydroxypiperidino, etc., and especially preferable cyclic amino is morpholino.
The xe2x80x9cprodrugxe2x80x9d means a compound, which can be hydrolyzed chemically or biochemically in the living body and converted into the compound of the present invention. For example, when the pyrrole derivative of the present invention has a carboxyl group, then a compound wherein said carboxyl group is converted into a suitable ester group is a prodrug thereof. Preferable examples of the ester are pivaloyloxymethyl ester, acetyloxymethyl ester, cyclohexylacetyloxy-methyl ester, 1-methylcylohexylcarbonyloxymethyl ester, ethyloxy-carbonyloxy-1-ethyl ester, cyclohexyloxycarbonyloxy-1-ethyl ester, etc.
The xe2x80x9cpharmaceutically acceptable saltxe2x80x9d includes, for example, an alkali metal salt such as sodium salt, potassium salt, etc., an alkaline earth metal salt such as calcium salt, magnesium salt, etc., an inorganic metal salt such as zinc salt, a salt with an organic base such as triethylamine, triethanolamine, trihydroxymethylaminomethane, amino acid, etc., when the pyrrole derivatives of the present invention or a pharmaceutically acceptable salt thereof have an acidic group. When the pyrrole derivatives of the present invention or a pharmaceutically acceptable salt thereof have a basic group, the pharmaceutically acceptable salt includes, for example, a salt with an inorganic acid such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, etc., a salt with an organic acid such as acetate, propionate, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, ascorbate, etc.
The pyrrole derivatives of the present invention and a pharmaceutically acceptable salt thereof exhibit TGF-xcex2 inhibitory activity and are useful as a fibrosis inhibitor for organs or tissues. To be more precise, the present compounds are useful as a medicament for treating the following diseases, which is caused by the fibrosis of organs or tissues.
Kidney diseases: diabetic renal disease, glomerular nephritis, tubulointerstitial nephritis, hereditary renal disease
Respiratory diseases: interstitial pneumonia, chronic obstructive pulmonary disease, asthma
Digestive diseases: cirrhosis hepatis, chronic pancreatitis, scirrhousgastric cancer
Cardiovascular diseases: myocardial fibrosis, restenosis after PTCA, arteriosclerosis
Bone-joint diseases: myelofibrosis, arthrorheumatism
Skin diseases: post-surgical scarring, burn scarring, keloid, hypertrophic scar, atopic dermatitis, scleroderma
Obstetrics diseases: uterus myoma
Urinary diseases: prostatomegaly
Other diseases: Alzheimer""s disease, sclerosing peritonitis, diabetic retinopathy, type 1 diabetes mellitus, Post-surgical organ adhesion
The pyrrole derivatives of the present invention may be prepared, for example, by the following process. 
wherein Ring Z, W2, Ar2, W1 and Ar1 are as defined above.
The present pyrrole derivatives can be prepared by binding the groups of Ar1xe2x80x94W1xe2x80x94 and Ar2xe2x80x94W2xe2x80x94 to Ring Z. The binding reaction of the groups Ar1xe2x80x94W1xe2x80x94 and Ar2xe2x80x94W2xe2x80x94 with Ring Z is carried out, for example, by the following reactions.
(1) Friedel-Crafts reaction
(2) Reaction of a compound having a multiple bond between carbon and carbon or an organic metal compound with an organic halide in the presence of a palladium catalyst
(3) Nucleophilic substitution to a corresponding organic halide
(4) Reaction of a carbonyl compound with an organic metal compound
(5) Reaction of a carboxylic acid derivative with an organic metal compound
(6) Wittig reaction, Horner-Emmons reaction
These reactions are listed just for illustration, and the present derivatives can also be prepared by other processes, based on the knowledge of a skilled person in the organic synthesis. Besides, in this process, firstly the groups for W2 or W1 are bound to Ring Z, and then the groups for Ar1 or Ar2 are bound to the resultant. The method for binding these groups can be the same ones as those for the reaction with Ring Z as mentioned above.
In each reaction as mentioned above, a function group can be protected if necessary. The protecting groups to be employed, and the conditions for protection or deprotection are disclosed in detail in the literature of Greene, et al., (T. W. Greene and P. G. M. Wuts, xe2x80x9cProtecting Groups in Organic Synthesisxe2x80x9d, 1991, JOHN WILEY and SONS, INC.)
Double bond, hydroxy group and carbonyl group, etc. being produced in each reaction as mentioned above are subjected to hydrogenolysis, reduction, oxidization, etc., if necessary. Besides, after each reaction as mentioned above, function groups may be converted into other function groups. The conversion reaction of these function groups is carried out, for example, according to the following articles.
Jikken Kagaku Koza (in Japanese, i.e, Experimental Chemical Lecture), vol. 19-26 (1992, MARUZEN CO., LTD.)
Seimitsu-Yuki-Gosei (in Japanese, i.e., Fine Organic Synthesis) (1993, Nankodo, Co., Ltd.)
Compendium of Organic Synthetic Methods, Vol. 1-9 (John Wiley and Sons)
Comprehensive Organic Synthesis, Vol. 1-9 (1991, Pergamon Press)
Comprehensive Organic Transformations (1989, VCH Publishers)
Survey of Organic Syntheses, Vol. 1-2 (1970, 1977, John Wiley and Sons)
For example, the reduction of the hydroxy group existing at the 1-position of the alkylene bound to Ring Z is carried out by using a combined reducing agent such as sodium borohydride/isopropanol, triethylsilane/trifluoroacetic acid, etc. The reaction solvent is, for example, tetrahydrofuran (THF), dioxane, dichloromethane, chloro-benzene, etc., and the reaction is carried out at a temperature of from about xe2x88x9220xc2x0 C. to a boiling point of the solvent to be used. The reduction of carbonyl into methylene is carried out, for example, by using a combined reducing agent such as sodium borohydride/isopropanol, hydrazine/potassium hydroxide or sodium hydroxide, zinc amalgam/hydrochloric acid, etc. The reaction solvent is, for example, THF, dioxane, etc., and the reaction is carried out at a temperature of from 0xc2x0 C. to a boiling point of the solvent to be used.
For example, the oxidization of hydroxy group existing at the 1-positin of the alkylene bound to Ring Z is carried out by using an oxidizing reagent such as manganese dioxide, etc., a composite oxidizing reagent such as 4-methylmorpholine-4-oxide/tetra-n-propylammonium perruthenate, etc. The reaction solvent is, for example, THF, dioxane, dichloromethane, chlorobenzene, chloroform, etc., and the reaction is carried out at a temperature of from about 0xc2x0 C. to a boiling point of the solvent to be used.
(1) Friedel-Crafts reaction 
wherein Ring Z is as defined above, Q is an organic group, and X is a chlorine, bromine, etc.
The Friedel-Crafts reaction is carried out, for example, according to J. Org. Chem., 48, 3214-3219 (1983), to introduce Q- on the carbon atom of Ring Z. In this reaction, preferable Q-X is, for example, an alkyl halide, an acid halide, etc. The reaction is carried out in the presence of a Lewis acid such as AlCl3, BF3.OEt2, ZnCl2, SnCl4, etc., in an inert solvent such as dichloromethane, dichloroethane, etc. and usually at a temperature of from room temperature to a boiling point of the solvent to be used.
When Ring Z is pyrrole ring, indole ring, pyrazole ring or imidazole ring, the Friedel-Crafts reaction is preferably carried out by firstly protecting the nitrogen atom at the 1-position with a phenyl-sulfonyl (or toluylsulfonyl) moiety. When the 1-position is protected with phenylsulfonyl moiety, the reaction is carried out, for example, by reacting with phenylsulfonyl chloride, etc. in the presence of a base such as NaH, etc. When Ring Z is a pyrrole ring protected with phenylsulfonyl, the reaction position can be controlled by the kind of a Lewis acid to be used. For example, by using AlCl3, the 3-position is reacted (J. Org. Chem., 48, 3214-3219 (1983)), and by using BF3.OEt2, the 2-position is reacted. After the Friedel-Crafts reaction, the phenylsulfonyl is removed by hydrolysis. For example, the phenylsulfonyl is removed by reacting in the presence of a base such as sodium hydroxide, potassium hydroxide, etc. in a mixed solvent of water and methanol, ethanol, etc. at a temperature of from room temperature to a boiling point of the solvent to be use.
(2) Reaction of a compound having a multiple bond between carbon and carbon or an organic metal compound with an organic halide in the presence of a palladium catalyst 
wherein Ring Z, Q and X are as defined above, M is a substituted tin atom, a substituted boron atom, etc., and Qxe2x80x2 is a corresponding organic group.
This reaction is carried out, for example, according to the methods disclosed in Synth. Commun., 11, 513 (1981), J. Am. Chem. Soc., 111, 314 (1989), J. Org. Chem., 52, 422 (1987), J. Org. Chem., 37, 2320 (1972), etc. To be more precise, the reaction is carried out by reacting a compound having a multiple bond between carbon and carbon or an organic metal compound with an organic halide in an inert solvent in the presence of a palladium catalyst, a base, etc. The palladium catalyst includes, for example, a palladium (II) catalyst such as Pd(OAc)2, PdCl2(PPh3)2, etc., and a palladium (0) catalyst such as Pd(PPh3)4, Pd(dba)2, etc. The base includes, for example, an inorganic base such as NaHCO3, K2CO3, etc., an organic base such as NEt3, iPr2NEt, Et2NH, etc., and the reaction can be accelerated by addition of a phosphine ligand such as PPh3, etc., a phase-transfer catalyst such as BnEt3NCl, etc., or an inorganic salt such as CuI, etc. The inert solvent includes, for example, N,N-dimethylformamide (DMF), THF, dioxane, toluene, etc. The reaction temperature is usually in the range of from around room temperature to a boiling point of the solvent to be used.
(3) Nucleophilic substitution to a corresponding organic halide 
xe2x80x83wherein Ring Z, Q and X are as defined above, M is an alkali metal atom, a magnesium halide, a zinc halide, etc.
This reaction is carried out according to the method disclosed in J. Org. Chem., 26, 3202 (1961). The organic metal compound containing Ring Z can be prepared, for example, by halogen-metal exchange reaction, or by removing hydrogen atom using a base, which is further reacted with Q-X.
When Ring Z is a pyrrole ring, an indole ring, a pyrazole ring or an imidazole ring, the group Q- can be introduced on the nitrogen atom of these rings by reacting in an inert solvent (e.g., THF, ether, DMF, etc.) in the presence of a base (e.g., NaH, KH, potassium t-butoxide, ethyl-magnesium bromide, butyl lithium, lithium 2,2,6,6-tetramethyl-piperidine, etc.). The reaction temperature is in the range of from about 0xc2x0 C. to about 80xc2x0 C.
(4) Reaction of a carbonyl compound with an organic metal compound 
xe2x80x83wherein Ring Z, Q and X are as defined above.
This reaction is carried out, for example, by the method disclosed in Tetrahedron, 26, 2239 (1970), J. Org. Chem., 55, 6317 (1990), etc. The organic metal compound in this reaction can be prepared in a similar manner to the preparation of the organic metal compound of the above (3). The organic metal compound thus obtained is reacted, for example, with an aldehyde in an inert solvent (e.g., THF, ether, toluene, etc.). The reaction temperature is in the range of from about xe2x88x92100xc2x0 C. to room temperature.
(5) Reaction of a carboxylic acid derivative with an organic metal compound 
xe2x80x83wherein Ring Z, Q and M are as defined above, Y is chlorine, an alkanoyloxy, an alkoxycarbonyloxy, an alkoxy, a dialkylamino, 2-pyridylthio, etc.
This reaction is carried out, for example, by the method disclosed in Org. Lett., 2, 1649 (2000). The organic metal compound in this reaction can be prepared in a similar manner to the preparation of the organic metal compound of the above (3) and (4). The organic metal compound thus obtained is reacted, for example, with a compound having an activated carbonyl group in an inert solvent (e.g., THF, ether, toluene, etc.). The reaction temperature is in the range of from about xe2x88x92100xc2x0 C. to room temperature.
(6) Wittig reaction, Horner-Emmons reaction 
xe2x80x83wherein Ring Z and Q are as dfined above, and Rxe2x80x3 is an alkyl.
This reaction is carried out, for example, by the method disclosed in Tetrahedron, 49, 1343 (1993). To be precise, an organic phosphorus compound (e.g., a phosphonium salt, a phosphoric acid ester, etc.) is treated with a base (e.g., NaH, BuLi, KOtBu, etc.) and reacted with a carbonyl compound in an inert solvent (e.g., THF, ether, dichloro-methane, etc.). The reaction temperature is in the range of from about xe2x88x92100xc2x0 C. to a boiling point of the solvent to be used.
For example, the following compound 8 is preferably prepared as follows: 
wherein R2, R3, R4 and R5 are as defined above, and Rxe2x80x2 is phenyl or 4-toluyl.
The compound 3 is prepared by reacting the compound 1 with the compound 2 in the presence of a Lewis acid in an inert solvent, according to J. Org. Chem., 48, 3214-3219 (1983). The 2-position of the pyrrole ring is advantageously preferentially reacted with the compound 2 by using BF3.OEt2, ZnCl2, SnCl4 as a Lewis acid. The inert solvent is preferably halogenated hydrocarbons such as dichloro-methane, dichloroethane, etc., and the reaction temperature is in the range of from about 0xc2x0 C. to a boiling point of the solvent to be used, and preferably around room temperature.
The compound 3 is hydrolyzed in the presence of a base to give the compound 4. The base includes NaOH, KOH, etc., and the solvent includes a mixed solvent of dioxane and water, a mixed solvent of methanol and water, etc. The reaction temperature is in the range of from about 50xc2x0 C. to about 90xc2x0 C.
The compound 4 is reacted with an allyl halide in an inert solvent in the presence of a base to give the compound 5. The base is preferably KOtBu, etc., and NaH can also be used. The inert solvent includes, for example, THF, DMF, etc., and the reaction temperature is in the range of about 40xc2x0 C. to about 60xc2x0 C.
The compound 6 wherein R4 is methyl is prepared by reacting the compound 5 with a Vilsmeier reagent (Org. Synth. Coll. Vol. IV, 831, etc.), followed by subjecting the product to reduction in a halogenated hydrocarbon solvent. The reduction is carried out, for example, by using triethylsilane-trifluoroacetic acid as a reducing agent, etc., and usually at a temperature of from about 0xc2x0 C. to around room temperature. The compound 6 wherein R4 is an alkyl group other than methyl is prepared by reacting the compound 5 with an alkanoyl halide in the presence of a Lewis acid, followed by reduction of the product. The Lewis acid includes AlCl3, etc., and the reaction is usually carried out at a temperature of from about 0xc2x0 C. to a boiling point of the solvent to be used.
The compound 8 is prepared by reacting the compound 6 and the compound 7 in the presence of a palladium catalyst and a base in an inert solvent. The palladium catalyst includes a palladium (II) catalyst such as Pd(OAc)2, etc., a palladium (0) catalyst such as Pd(dba)2, etc. The base includes NaHCO3, K2CO3, triethylamine, etc., and the reaction can be accelerated by addition of a phosphine ligand such as PPh3, etc., a phase-transfer catalyst such as BnEt3NCl, etc. The inert solvent includes DMF, THF, toluene, etc., and the reaction temperature is usually in the range of from room temperature to a boiling point of the solvent to be used.
The present invention also includes hydrates and solvates such as ethanolates of the present pyrrole derivatives, a prodrug thereof, and a pharmaceutically acceptable salt thereof. When the pyrrole derivatives, etc. of the present invention exist in the form of an optical isomer, a stereoisomer, an enatiomer, then the present invention also includes each isomer or a mixture thereof. In order to obtain an optical isomer of the present compound, the present pyrrole derivatives, etc. are converted into a salt with an optically active acid (e.g., mandelic acid, N-benzyloxyalanine, lactic acid, tartaric acid, o-diisopropilidene tartrate, malic acid, camphor sulfonic acid, bromo camphor sulfonic acid, etc.) or an optically active amine (e.g., xcex1-phenethylamine, kinin, quinidine, cinchonidine, cinchonine, strychnine, etc.), and the precipitated crystals are collected by filtration, and further converted into a free compound.
The pyrrole derivative of the present invention, or a prodrug thereof, or a pharmaceutically acceptable salt thereof can be administered either orally or parenterally. The pharmaceutical composition for oral administration includes, for example, tablets, pills, granules, powders, capsules, cachets, liquids, suspensions, emulsions, syrups, etc. The pharmaceutical composition for parenteral administration includes, for example, injections (e.g., intravenous injection, intramuscular injection, etc.), percutaneous formulations (e.g., creams, ointments, lotions, patches, matrixes, etc.), intranasal formulations, rectal formulations (e.g., suppositories, etc.), etc.
These formulations are prepared by a conventional method.
Oral solid preparations such as tablets are prepared, for example, by mixing the present pyrrole derivative, etc., with excipients (e.g., lactose, D-mannitol, sugar, corn starch, cellulose, calcium hydrogen-phosphate, etc.), disintegrants (e.g., calcium carmerose, low substituted hydroxypropyl cellulose, crosscarmerose sodium, sodium carboxy-methyl starch, carboxymethylcellulose sodium, starch sodium glycolate, etc.), binders (e.g., polyvinylpyrrolidone, polyvinyl alcohol, hydroxy-propylcellulose, hydroxypropylmethylcellulose, methyl cellulose, etc.), lubricants (e.g., magnesium stearate, talc, magnesium stearate, etc.), flavors and corrigents, stabilizers, coloring agents, etc., and formulated into tablets, granules, powders, capsules, etc. by a conventional method.
Oral liquid preparations are prepared, for example, by adding the present pyrrole derivative, etc. into water, and further adding thereto a coloring agent, a flavor, a stabilizer, a sweetening agent, a solubilizer, a thickening agent, etc. if necessary. The thickening agent includes, for example, a pharmaceutically acceptable natural or synthesized gum, resin, methyl cellulose, sodium carboxymethyl cellulose, or a conventional suspending agent, etc.
Injections are prepared by dissolving or suspending the present pyrrole derivative, etc. into a pharmaceutically acceptable carrier such as water, a physiological saline, an oil, aqueous glucose solution, etc., and further adding thereto as a coadjuvant a pH adjuster, a buffer, a stabilizer, a solubilizing agent, an emulsifier, etc. if necessary.
The dosage and the frequency of administration of the present pyrrole derivative, etc. may vary according to the diseases, ages, weights of the patients and the administration form, etc., but the present compounds can usually be administered orally in a dose of about 1 to about 500 mg per day, preferably in a dose of about 3 to about 300 mg per day, especially preferably in a dose of about 5 to about 100 mg per day, in adult (body weight: 60 kg), once a day, or divided into several dosage units. When the present compound is administered in an injection preparation, the dosage thereof is in the range of about 0.1 to about 300 mg per day, preferably in the range of about 1 to about 100 mg per day, in an adult (body weight: 60 kg), once a day, or divided into several dosage units, or continuously.